INDUCTION OF T-CELL UNRESPONSIVENESS BY ANTI-CD3 ANTIBODIES OCCURS INDEPENDENTLY OF COSTIMULATORY FUNCTIONS

Antibodies to the T cell receptor (TcR)-associated CD3 molecules repre sent potent immunosuppressive agents in vivo in both human and animals models, in spite of their well-characterized mitogenic properties. We demonstrate in this report that antibodies to the B7.2 molecule inhib it IL-2 production in vivo caused by anti-CD3 administration, suggesti ng that anti-CD3 monoclonal antibodies (mAb) stimulate naive T cells i n vivo in a co-stimulation-dependent fashion. To characterize better t he mechanisms by which antibodies to CD3 induce antigen unresponsivene ss in naive T cells, we developed a model of activation-induced T cell unresponsiveness in vitro. Our data indicate that following interacti on with mitogenic anti-CD3 mAb in vitro, naive purified CD4(+) T cells become refractory to a further stimulus. This unresponsive state deve lops independently of co-stimulatory functions, as neither B7-expressi ng antigen-presenting cells nor anti-CD28 mAb are able to prevent aner gy induction in this model. We therefore conclude that induction of un responsiveness in naive T cells by anti-CD3 mAb is not a consequence o f co-stimulus-deficient stimulation, but may develop following a produ ctive response both in vivo and in vitro. Unresponsive T cells display a defective calcium mobilization upon TcR triggering. suggesting that anergy is maintained in these cells through receptor desensitization. The potential role of co-stimulation-independent TcR desensitization in the down-regulation of immune responses in vivo is briefly discusse d.